SILVER SPRING, MD. – Considering reports of severe reactions following testosterone undecanoate injections, advisers to the Food and Drug Administration were evenly divided over the question of whether this risk rendered the product unsafe for use in the United States, as replacement therapy for men with hypogonadism.
The FDA is considering the approval of this long-acting testosterone – which has been available outside of the United States since 2003 – and convened the meeting of two advisory panels to review the safety data and the company’s plans for managing this risk, if approved in the United States.
Efficacy is not an issue: The agency has concluded that the 750-mg intramuscular dose of testosterone undecanoate, administered once every 10 weeks, meets the regulatory requirements for efficacy for a testosterone replacement product, based on results of serum testosterone levels in the single U.S. open-label study of 131 patients. But cases of anaphylaxis and pulmonary oil microembolism (POME), during or shortly after injections are administered, reported in clinical and postmarketing studies in countries in which it has been approved, has held up approval in the United States since Endo Pharmaceuticals filed for approval in 2007.
At the April 18 meeting, the FDA’s Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committee voted 9-9, when asked whether they believed that testosterone undecanoate (TU), a long-acting depot formulation of testosterone in castor oil and benzyl benzoate, was safe for the indication under review: replacement therapy in adult men for conditions associated with an absence or deficiency of endogenous testosterone. Those who felt the safety profile was acceptable for approval were concerned that the product was being held to a higher standard than other FDA-approved injectable testosterone products, which have labels that list anaphylaxis as a possible risk, and cited extensive use of the drug for years in Europe and no reports of deaths from these severe reactions.
But those voting no said that while they appreciated the need for a long-acting testosterone injection, there were not enough data to fully evaluate its safety and it was not possible to identify who is at an increased risk for having severe reactions. And, once approved, it might be used outside of the indication and would increase risk.
To address the risks of anaphylaxis and pulmonary oil microembolism (POME), Endo Pharmaceuticals has proposed that the injection be administered slowly, over 30 to 60 seconds in a physician’s office, and that patients be observed for 30 minutes afterward, with these instructions included in the product label. But the FDA panels voted 17-1 that this would not be sufficient to ameliorate this risk, calling for more interventions, including a black box warning, a training program for physicians who administer the injections to ensure they understand the severe risks (which could include an online course), and a more narrow indication to limit inappropriate use.
Although it makes sense clinically, "We don’t know the cause of this, so how can we know how to ameliorate this?" said panelist Dr. Richard Bockman, head of the endocrine service at the Hospital for Special Surgery, New York.
The features of POME are a cough or dyspnea, with or without other symptoms that can also include throat irritation, malaise, profuse sweating, chest pain, dizziness, paresthesia or syncope, which occurs within 24 hours of the injection, according to the FDA.
The company’s risk evaluation and mitigation strategy (REMS) includes physician and patient education and controlled distribution to health care providers for administration only in the office, with a 30-minute wait after the injection.
But Suzanne Robottom, Pharm.D., a senior risk management analyst in the FDA’s division of risk management, said that in Europe, cases of POME continue to be reported despite recommendations to administer the injection slowly and observe patients for 30 minutes. The agency is concerned that implementing the measures proposed by the company, which include prescribing and distribution restrictions, would pose an undue burden "for a drug with limited additional benefit," she added.
An FDA review of 199 postmarketing cases of POME, between November 2003 and April 2012, determined that 84 were severe, with severe dyspnea, loss of consciousness, circulatory collapse, or loss of bowel function. Many cases started as the medication was being injected. Although no deaths were reported, the long-term cardiopulmonary effects of severe cases or chronic effects of repeated less-severe episodes are not known, according to the FDA. During 2003-2011, there were 53 postmarketing cases of anaphylaxis reported, using a conservative definition.
Dr. Allan Glass